The ability of Herpes simplex virus (HSV) vectors to induce selective death of brain tumor cells in vivo may be due to a number of different mechanisms, including direct virus-induced oncolysis, sensitization of the tumor to chemotherapy-induced cell death or induction of immune responses directed against the vector of tumor antigens. At present, little is known about the relative contribution of these different mechanisms of about immune responses, directed against HSV vectors. Cellular immune responses to HSV vectors may augment viral oncolysis; alternatively, they may inhibit oncolysis by limiting replication of the vector. Addressing these issues is critical to the successful development of HSV vectors for gene therapy for brain tumors, since the answers to these questions can result in a modification to either augment of diminish immunogenicity resulting in improved oncolysis. We propose to address this issue through the following set of specific aims: 1. To examine the effect of the host immune response on tumor cell killing in mice using the model glioma GL261; 2. To determine the immune mechanism of tumor cell killing in this model; 3. To characterize CTL responses to HSV mutants following intracerebral injections in Aotus monkeys; and 4. To characterize the specificity of tumor infiltrating lymphocytes (TILs) in recognizing viral mutants and/or tumor in patients affected by malignant glioma. The results from these experiments should shed light on potential beneficial or adverse interactions between the immune system and viral oncolysis and ultimately assist in the development of more effective HSV vectors for the treatment of brain tumors.